Colorectal cancer (CRC) is the second most lethal malignancy in the USA and affects over a million people every year. A significant CRC health disparity exists between African Americans (AA), American Indians (AI) and Caucasians (CA) in relation to its occurrence, drug response and mortality. Due to this, the overall mortality is highr among AA/AI compared to CA. However, the underlying molecular mechanisms of this disparity in AA/AI are not known. Therefore, it is highly imperative to understand the molecular basis and the identification of biomarker(s) that can be used for early stage diagnosis, metastasis and drug response to reduce this unacceptable health disparity. Our laboratory has identified a novel transmembrane mucin, MUC13, which is highly overexpressed/aberrantly localized in CRC and is involved in its pathogenesis. Additionally, our recent preliminary data suggest a markedly higher and aberrant expression of MUC13 in AA/AI CRC samples compared to CA counter parts. We have shown that MUC13 is an important modulator of several signal-transduction pathways and affects multiple key proteins involved in cell growth and survival, such as sonic hedgehog, HER2 and p53. Our published and preliminary studies have suggested an aberrant expression of MUC13 which has implications in CRC progression and metastasis. Based on these compelling evidence, we hypothesize that the differential/aberrant expression of MUC13 and/or MUC13 variants are underlying factors associated with CRC health disparity. In addition, we hypothesize this differential MUC13 expression is regulated by certain microRNAs (miR-145 and miR-132) and inflammatory mediators produced by the tumor microenvironment (e.g. interleukin-6 mediated STAT5B phosphorylation) resulting in malignant colorectal cancer cells phenotypes among AA/AI populations. Three specific aims with comprehensive experimental approach are proposed to test this hypothesis. In Aim 1, we propose to study the expression profile of MUC13 in Caucasians, African Americans and American Indians CRC tissues and its correlation with disease progression, metastasis and patient survival. Aim 2 will investigate the presence of MUC13 spliced variants/single nucleotide polymorphisms (SNPs) and their association with chemoresistance, metastasis and CRC health disparity. Aim 3 intends to elucidate the molecular mechanisms of MUC13 regulation in clinically relevant CRC tissues and cell line models. We will also investigate how various intrinsic factors can induce aberrant/ altered subcellular localization of MUC13, in clinically relevant CRC cell line models, as aberrant subcellular localization (cytoplasmic, nuclear) of MUC13 has also been associated with disease stage, prognosis and metastasis. The results of this multi factorial study will determine if MUC13 can be used as a molecular signature for early detection of aggressive and metastatic CRC in AA and AI. This comprehensive study will further provide important insights regarding MUC13 etiology in CRC and help in designing preventive and therapeutic strategies to reduce CRC mortality and CRC health disparity in underserved populations.